TCF21 expression controls murine spleen organogenesis
Abdominal histological sections of wild-type (left) and TCF21 mutant embryos (center and right: dorsal and ventral regions of the developing spleen) at E12.5 reveal extensive apoptosis (indicated by yellow staining) in the splenic primordium of TCF21 mutant mice. p, pancreas; s, spleen; st, stomach.
With courtesy of Dr. Eric Olson, PNAS, 97, 9525-30 (2000)

We recently identified transcription factor 21 or TCF21 as a novel candidate tumor suppressor gene on chromosome 6q23-24, a region frequently lost in head and neck squamous cell carcinoma (HNSCC) and other malignancies.

TCF21 is a frequent target for altered DNA methylation in human tumors and is transcriptionally silenced by DNA methylation.

We have now preliminary data supporting our hypothesis that TCF21 is a novel tumor and possibly a metastasis suppressor gene.
To address this hypothesis, we propose three specific aims.

(1) In aim 1 we will investigate expression patterns of TCF21 and possible alternative splice forms in various normal tissues and cancer cell lines and evaluate in detail how DNA methylation contributes to DNA silencing. We will next evaluate the mutational spectrum of TCF21 in HNSCC and lung cancer to determine the importance of TCF21 silencing in each tumor type.

(2) In aim 2 we propose experiments that will help to understand how TCF21 contributes to tumorgenesis and identify binding partners and target genes specific for different tissues using a combination of expression array, ChIP, yeast two hybrid and luciferase assays.

(3) In aim 3 we will utilize mouse models to further investigate the role of TCF21. We are planning nude mouse tumorigenicity and metastasis assays, we are proposing a carcinogenesis experiment with Tcf21 heterozygous knock out mice; and will investigate Tcf21 and downstream targets in a mouse model for oral cavity carcinogenesis and lung carcinogenesis.

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